The aim of the research is to identify a human beta globin gene which can be regulated in a normal fashion after introduction into hematopoietic cells by retroviral transduction. Such research could provide the basis for a protocol of somatic gene therapy for patients with the severe inherited hemolytic anemias thalassemia major and sickle cell disease. Human globin genes in various configurations will be added to replication-defective retroviruses which also carry the gene for a dominant selectable marker such as resistance to the neomycin analogue G418 or the gene for a mutant dihydrofolate reductase which confers resistance to methotrexate. Human marrow cells as well as marrow from two animal model systems (mouse and dog) will be infected with globin containing retroviruses and the developmental activation, tissue or cell specificity, ultimate level, and persistence of globin expression will be studied. Assays will focus on the structure of the transduced globin gene, its transcripts, the amount and quality of the globin chains produced, and the effects on erythroid and nonerythroid cells. Assays for helper virus will be performed to help assess the risk of viral-induced disease. Experiments in the mouse will test whether pluripotential stem cells can accept a human globin gene and the stringency with which the human gene is activated in different hematopoietic lineages. Studies in the dog will extend these results in a larger animal which is a realistic model for human bone marrow transplantation. Studies with cultured human marrow may reveal if a therapeutic transduced globin gene can be expressed appropriately, and help refine infection protocols and efficient assays which could become the basis for a somatic therapy scheme centered on viral infection of bone marrow as an autologous transplant.